We propose to investigate the predictive roles of endogenous sex steroid hormones and gene polymorphisms in the sex-hormone genes in the development of colorectal cancer among postmenopausal women who were not using hormone therapy at blood collection and among middle-aged and older men. Several lines of evidence have suggested that sex hormones and sex steroid receptors may be attributable to sex-related differences in colorectal cancer development with respect to prevalence, tumor location, and response to several risk factors. We will utilize archived blood samples from four large cohorts in the Nurses'Health Study (NHS), Women's Health Study (WHS), Health Professionals Follow-Up Study (HPFS), and Physicians'Health Study II (PHS II). Through year 2010, at least 670 female and 604 male incident cases of colorectal cancer for a total of at least 1,274 cases would have occurred in the four cohorts. Within each cohort, controls will be 1:1 matched to the cases and will be randomly selected from participants who are at risk for the disease at the time when the matched case occurred. We are going to evaluate endogenous circulating levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), non-SHBG-bound T, and non-SHBG-bound E2 in relation to colorectal cancer incidence. Because the synthesis of sex hormones are affected by obesity, which also elevates insulin levels and leads to an increased risk of colorectal cancer, we aim to control for the effects of insulin in conditional logistic regression models by including plasma c-peptide, an indicator for endogenous insulin levels. We are also going to evaluate gene polymorphisms in androgen receptor (AR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), progesterone receptor (PGR), and SHBG in relation to colorectal cancer risk using both functional and haplotype tagging-SNPs approaches. This is the first investigation of the etiological role of endogenous sex hormones in the development of colorectal pathogenesis among postmenopausal women and men. The prospective design, high follow-up rates, and detailed information on lifestyle and dietary exposures also make this study highly cost-efficient. PUBLIC HEALTH RELEVANCE: Findings from this study will provide valuable information on the etiology of colorectal cancer, leading to new strategies for identifying men and women at risk. Clarifying the role of sex hormones in colorectal cancer would also permit new approaches for colorectal cancer prevention and ultimately contribute to the development of novel therapeutic options for patients suffering from colorectal cancer.